key: cord-0824743-gxm9zlmf
authors: Ceriello, Antonio; De Nigris, Valeria; Prattichizzo, Francesco
title: Why is hyperglycemia worsening COVID‐19 and its prognosis?
date: 2020-05-28
journal: Diabetes Obes Metab
DOI: 10.1111/dom.14098
sha: 0e1d725e766218e291e0bb240779e74a49b843cb
doc_id: 824743
cord_uid: gxm9zlmf

nan

Hyperglycemia, even in people without previous diabetes, has been often reported in the complicated "Corona Virus Disease 2019" (COVID-19) 1-2 . Hyperglycemia in COVID-19 is a strong predictor of worsening the prognosis and increasing the possibility to die [1] [2] . Therefore, understanding the process behind this evidence may be of great interest.

It is known that "Severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2) may infect endocrine pancreas cells via their expression of ACE2 receptors 3 . It is possible that the pancreatic damage, due to the virus, and the resultant impairment in β-cell insulin secretion may worsen preexisting diabetes or may determine the appearance of hyperglycemia in non-diabetes 3 . Interestingly, the Severe Acute Respiratory Syndrome (SARS) in 2003, caused by another coronavirus closely related to COVID-19, also produced a transient impairment of pancreatic islet cell function 4 . Cytokines, including IL-6 and TNFα, have been found to be elevated in the patients with severe COVID-19 5 . Inflammation generates insulin resistance 6 . Therefore, it is possible that during COVID-19, due to the huge production of cytokines, insulin resistance may be exacerbated or de novo induced. This phenomenon may also contribute to the appearance of hyperglycemia. Interestingly, cytokines may, in turn, also affect β-cell function, contributing to a further decrease of insulin secretion 6 . Therefore, the generation of a vicious circle may be possible:

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SARS-CoV-2 infection, through a decrease of both insulin secretion and the appearance/worsening of insulin resistance, may induce hyperglycemia, which, in turn, may further damage β-cells and worsens insulin resistance ( Figure 1 ).

When generated, hyperglycemia may also play a direct role in worsening the SARS-CoV-2 infection. The non-enzymatic glycation is a reaction exacerbated by hyperglycemia; the glycation of the ACE2 is needed for the linkage of the virus to this cellular receptor 7 . Therefore, high and aberrantly glycated ACE2 in the tissues in uncontrolled hyperglycemia might favor the cellular intrusion of SARS-CoV2, leading to a higher propensity to COVID-19 infection and a higher disease severity 7 .

However, hyperglycemia not only may worse the COVID-19, but also may be directly involved in favoring a bad outcome of the disease. An increase of glycemia is accompanied by an overproduction of inflammatory mediators 8 , which are very dangerous for the cardiovascular system. Acute hyperglycemia, through the glycation process, may also alter the function of some key proteins (e.g. antithrombin III) involved in protecting from thrombus generation 9 . At the same time, through oxidative stress generation, an acute increase of glycemia may induce endothelial dysfunction and thrombosis [8] [9] [10] , which, in turn, may produce generalized organ damage, as described in the COVID-19 1 .

Accordingly to this view, it is evident that a fast tight control of hyperglycemia during the early phase of COVID-19 might be decisive. Normalizing blood glucose levels may stop the vicious circle, due to hyperglycemia, which, is leading to a worsening of the disease as described in the Figure 1 . This, probably, may improve the situation, giving more hope for the recovery from the disease.

SARS-CoV-2 may affect β-cells producing a reduction of insulin secretion.

SARS-CoV-2 infection is also accompanied by a huge production of cytokines, which can induce insulin resistance. Both, reduced insulin secretion and insulin resistance, may hesitate in hyperglycemia, which in turn, may further decrease insulin secretion and increase insulin resistance.

Hyperglycemia is also generating non-enzymatic glycosylation. Glycosylation of the ACE2 receptor can facilitate the entry of the SARS-CoV-2 in the host cells.

On the other hand, glycosylation of antithrombin III may favor thrombus formation.

Acute hyperglycemia, through cytokines production or directly may provoke endothelial dysfunction and thrombus formation, which in turn can lead to organ damage and fatal outcome of the disease.

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The clinical characteristics and outcomes of diabetes mellitus and secondary hyperglycaemia patients with coronavirus disease 2019: a single-center, retrospective, observational study in Wuhan

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